This application addresses Recovery Act Limited Competition: Research to Address the Heterogeneity in Autism Spectrum Disorders (R21) with RFA-MH-09-172. Autism spectrum disorders are among the most heritable common disorders and show extensive clinical heterogeneity, however, both the underlying neurobiological basis and genetic architecture are poorly understood. Four times as many males as females are affected, for unknown reasons. Thus, we may be able to leverage our knowledge about the primary genetic and hormonal determinants of sexual dimorphism in order to dissect a major source of heterogeneity in autism. The long-term goal is to use genetic tools to better understand the biological basis of autism, leading to advances in diagnosis, prevention and treatment. The objective of this proposal is to investigate genetic causes for increased male risk of autism. The central hypothesis is that sexually dimorphic susceptibility to autism is reflected in sex differences of the genetic architecture of autism. Guided by preliminary data including sex-specific genetic contributors to autism and extensive sexually dimorphic genetic architecture for numerous human traits, this proposal comprises a pilot to recruit subjects and compare males and females in order to distinguish genetic models and to identify sex-specific susceptibility loci. The specific aims include: 1) Recruitment of an enriched female-affected family sample, 2) Investigation of the genetic architecture of autism in females vs. males, and 3) Identification of the sex-specific genetic mechanisms or pathways involved in autism. The first aim will be accomplished by enrolling subjects retrospectively and prospectively from the UCSF Autism Clinic, enrolling subjects from an online autism community, and performing genome-wide SNP and CNV genotyping using the Affymetrix 6.0 microarray. The second aim will be accomplished by comparing family history, ascertainment, and measures of autism traits as well as comparing copy number profiles and summary SNP association signal between males and females. The third aim will be accomplished by analysis of sex-specific association signals, epistasis including X chromosome loci, and hormone-regulated gene pathway association. This approach is innovative, as sex-specific genetic architecture has not been comprehensively analyzed in a well-powered dataset, and we thus expect to gain novel insight into an important source of heterogeneity in autism. The results will be significant, as information about what protects females from developing autism could lead to reduction of male risk. PUBLIC HEALTH RELEVANCE: Autism is a common cause of severe disability to individuals and families across the lifespan with extremely limited treatment options. With better understanding of the biological basis and the genetic architecture of autism, diagnosis, prognosis, prevention and treatment options could be improved.